Need a New Heart? Make Like a Worm + Grow Your Own
WHY YOU SHOULD CARE
Because a cute little cross-eyed worm might offer clues to regrowing damaged tissues, organs and even limbs.
By David M. Garcia
In a classic episode of The Simpsons, Homer, ineffectual as usual, tries to steal snacks from a pair of vending machines by reaching his arms inside, only to end up completely stuck. When confronted with the possibility that sawing his arms off might be the only solution, he asks worriedly, “They’ll grow back, right?”
No, Homer, our limbs can’t just grow back like hair or fingernails. Yet some animals have amazing powers of regeneration. Lizards, salamanders, crabs and starfish can all regenerate lost appendages.
But the all-time champion of regeneration is a flatworm known as planaria. Cuter than most worms, planaria have a pair of cartoon-like crossed eyes and well-developed nervous systems and musculature. Brutal as it sounds, the magic happens when you slice off a planarian’s head; in just one week, it will grow a new one, fully formed and fully functional. That’s right: eyes, brain, the whole deal.
Could these findings in planaria give our relatively modest regenerative abilities an added boost?
Scientists are already learning big lessons from these tiny critters. One hope is that these types of studies could one day lead to transformative medical applications — like how to regrow skin for burn victims, or organ regeneration for patients otherwise dependent on transplantations. While their remarkable regenerative ability has been known for more than a century, it wasn’t until recently that technological advances have enabled biology labs to tackle this phenomenon head-on, literally.
Using cutting-edge methods to manipulate planarian genes, and an endless supply of razor blades, scientists are uncovering the basis of this remarkable trait. If we dream of one day tuning our human bodies to better regenerate damaged tissues, organs or even entire body parts, we must first learn from the humble planaria.
The promising possibilities of tissue regeneration are being explored in the labs of molecular biologists like Peter Reddien. Reddien’s lab at MIT seeks to answer two fundamental questions about planarian regeneration. First: Which cells have the ability to regenerate tissue? And second: How are they instructed to do so?
Reddien’s group showed that a specific population of adult stem cells, known as clonogenic neoblasts, can give rise to new tissue. Even a single clonogenic neoblast — capable of dividing numerous times into more specialized cells — is sufficient to regenerate any missing body part. Planaria are actually loaded with these stem cells, which are distributed throughout their bodies, ready to rapidly regenerate almost any missing body part.
How does a split worm know whether to grow a head or tail?
So how do clonogenic neoblasts know what to make? “The instructions they are given are in large part coming from non-neoblast cells,” says Reddien. For example, his lab, which is also part of the Whitehead Institute and the Howard Hughes Medical Institute, recently found that a certain type of muscle cell broadly distributed throughout the body appears to represent a system of coordinates for regeneration, sending signals to stem cells that direct them to the injury site, where they then regenerate the damaged or missing tissue.
As a postdoctoral researcher in Alejandro Sanchez-Alvardo’s lab at the University of Utah, Reddien used a method called RNA interference to block more than a thousand planarian genes, one by one. Hundreds of these genes, when blocked, led to gross defects in regeneration. Most of these genes are also present in our own genomes. Building on this approach, Christian Petersen, a postdoctoral researcher in Reddien’s lab at MIT, examined which of these genes were essential for distinguishing a head from a tail following injury.
Cleaving a planarian in half with a razor blade isn’t as barbaric as it might seem. In fact, it mimics one way these worms can reproduce, which involves attaching their tail to a surface and propelling their head forward with enough force to literally split themselves in two. Both pieces regenerate their missing parts, yielding two identical clones. But how does each wound know whether to grow a head or tail?
Humans are actually pretty good at regenerating tissue for the vast majority of injuries we face…
Petersen found that one gene, called ß-catenin, was critical. ß-catenin — which is found in many animals, including humans — allows cells to communicate with neighboring cells. This communication is especially important for ensuring that each tissue develops properly as an organism matures from an embryo into an adult. When Petersen inactivated ß-catenin in a worm and then cut it in half, the portion that retained a head regrew a second head instead of a tail, creating a two-headed worm. “Active ß-catenin was therefore required at wound sites to prevent head regeneration,” says Reddien. Two other labs produced similar results.
When Petersen made yet more incisions along the flank of a worm lacking ß-catenin, he ended up with a freakishly Franksteinian creature: a six-headed worm — suggesting that “make a head” instructions are expressed along large sections of the body. ß-catenin normally blocks these instructions at injuries along the sides and near the tail. So how do the instructions remain “on” when a worm has actually lost its head? Petersen discovered that another gene, notum, blocks the activity of the ß-catenin gene near head wounds, permitting growth of a new head only when necessary.
Humans are actually pretty good at regenerating tissue for the vast majority of injuries we face during our lifetimes, be it scrapes or broken bones. But for complex injuries that severely damage tissues, organs, or body parts, our bodies don’t have answers. Could scientists use their findings in planaria to give our relatively modest regenerative abilities an added boost? Reddien, a tall, straight-talking Texan, notes, “It’s too early to know specifics of how this research might help, but certainly finding and understanding the molecules that bring about certain key events in regeneration will allow us to look at what’s happening at human wounds.”
For the thousands of patients in need of organ or tissue transplants, it’s a potentially life-changing first step — all thanks to a simple flatworm.
David M. Garcia is a postdoctoral research fellow in Chemical and Systems Biology at Stanford University School of Medicine.
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